21-44551344-G-A

Variant names:

• chr21-44551344-G-A
• NM_198693.4:c.115C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198693.4(KRTAP10-2):​c.115C>T​(p.Pro39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP10-2 NM_198693.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

KRTAP10-2 (HGNC:22967): (keratin associated protein 10-2) This gene encodes a member of the high sulfur-type keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. This gene is located in a cluster of similar genes on 21q22.3. Alternatively-spliced transcript variants have been identified. [provided by RefSeq, Jan 2015]

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23469284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-2	NM_198693.4	c.115C>T	p.Pro39Ser	missense_variant	Exon 1 of 1	ENST00000391621.1	NP_941966.1
TSPEAR	NM_144991.3	c.303+16441C>T		intron_variant	Intron 2 of 11	ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2	c.99+16441C>T		intron_variant	Intron 3 of 12		NP_001258966.1
KRTAP10-2	NR_130165.2	n.126+36C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP10-2	ENST00000391621.1	c.115C>T	p.Pro39Ser	missense_variant	Exon 1 of 1	6	NM_198693.4	ENSP00000375479.1
TSPEAR	ENST00000323084.9	c.303+16441C>T		intron_variant	Intron 2 of 11	1	NM_144991.3	ENSP00000321987.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 159

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115C>T (p.P39S) alteration is located in exon 1 (coding exon 1) of the KRTAP10-2 gene. This alteration results from a C to T substitution at nucleotide position 115, causing the proline (P) at amino acid position 39 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Benign	0.19
Sift	Uncertain	0.029	D
Sift4G	Benign	0.11	T
Polyphen		0.15	B
Vest4		0.17
MutPred		0.61		Gain of glycosylation at P39 (P = 0.0502);
MVP		0.067
MPC		0.32
ClinPred		0.50	T
GERP RS		3.4
Varity_R		0.27
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-45971227;